Enantioselective Conjugate Additions of α‑Amino Radicals via Cooperative Photoredox and Lewis Acid Catalysis Laura Ruiz Espelt, Iain S. McPherson, Eric M. Wiensch, and Tehshik P. Yoon* Department of Chemistry, University of Wisconsin−Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States S Supporting Information *

functionalized radical intermediates. More recently, several groups have shown that transition metal photoredox sensitizers can be used to produce α-amino radicals under visible light irradiation.11 Although the utility of these amine-functionalized radical species in the synthesis of complex alkaloids has long been appreciated,12 methods to control the enantioselectivity of their addition reactions are extremely rare. To the best of our knowledge, the only prior example of an asymmetric reaction in this class is a single, elegant addition reaction reported by Bach in which a chiral hydrogen-bonding photosensitizer catalyzes the intramolecular conjugate addition of a photogenerated α-amino radical to a quinolone scaffold.13 A more general method to control the stereochemistry of such additions, particularly in an intermolecular context, is an unrealized goal with great synthetic potential. We recently reported the photocatalytic functionalization of N-aryl tetrahydroisoquinolines via an α-amino radical intermediate.8 This study provided two important observations that informed the design of our exploratory investigations. First, we found that the conjugate addition of the α-amino radicals to Michael acceptors was catalyzed by Brønsted acids. If chiral Lewis acids could have a similar effect, they might also control the stereochemistry of these additions.14 Indeed, Sibi, Porter, and others have established that chiral Lewis acids can dictate the enantioselectivity of radical conjugate additions,15 although these investigations have been limited to simple, unfunctionalized alkyl radicals. Second, we found that the rate-limiting step was a chainpropagating H atom abstraction process that was only efficient with N-aryl tetrahydroisoquinoline substrates with especially activated α-amino C−H bonds. We wondered if this narrow restriction on viable substrates could be overcome by an alternative method for generating the α-amino radical. In particular, we were inspired by Mariano’s insight that α-silyl amines undergo facile oxidative fragmentation and generate αamino radicals several orders of magnitude more efficiently than their nonsilylated analogues.9e Thus, the optimization of the enantioselective α-amino radical addition began with an exploration of the reaction between αsilylmethyl aniline 1 and crotonyl oxazolidinone 2a (Table 1). Irradiation with a household 23 W fluorescent light bulb in the presence of 2 mol % Ru(bpy)3Cl2 resulted in the slow formation of the expected radical conjugate addition product 3a in 28% yield after 18 h (entry 1). In accord with our initial hypotheses, Sc(III)-pybox complexes provided both a significant increase in the rate of the reaction and modest enantioselectivity (entries 2−

ABSTRACT: We report the highly enantioselective addition of photogenerated α-amino radicals to Michael acceptors. This method features a dual-catalyst protocol that combines transition metal photoredox catalysis with chiral Lewis acid catalysis. The combination of these two powerful modes of catalysis provides an effective, general strategy to generate and control the reactivity of photogenerated reactive intermediates.


hile photochemistry has long been appreciated as a powerful tool in organic synthesis,1 stereocontrol in photochemical reactions remains a significant challenge with few general solutions.2 A number of novel dual catalytic systems have recently been developed to address this long-standing problem. The combination of transition metal photoredox catalysts with chiral amine,3 carbene,4 and Brønsted acid organocatalysts5 has enabled a number of highly enantioselective photoinduced reactions. We recently reported the first method combining photoredox and chiral Lewis acid catalysis in the context of an asymmetric [2 + 2] photocycloaddition.6 Compared to organocatalysts, chiral Lewis acids possess a greater diversity of structures known to provide effective enantiodifferentiating environments for a wide range of mechanistically distinct organic reactions.7 We wondered if the ability to combine organic chemists’ detailed understanding of asymmetric Lewis acid catalysis with the emerging versatility of photoredox activation might provide a robust approach to controlling stereochemistry in photocatalytic reactions. Herein, we report our application of the principle of cooperative Lewis acid−photoredox catalysis to highly enantioselective reactions of α-amino radicals (Scheme 1). Our group has an established interest in the chemistry of αamino radicals.8 Pioneering studies by Mariano9 and Pandey10 demonstrated that the photosensitized oxidation of amines, αamino acids, and α-silylamines offers the most straightforward method for the production of these highly nucleophilic, Scheme 1. Design Plan for Cooperative Lewis Acid− Photoredox Catalysis of α-Amino Radical Additions

Received: December 15, 2014

© XXXX American Chemical Society


DOI: 10.1021/ja512746q J. Am. Chem. Soc. XXXX, XXX, XXX−XXX


Journal of the American Chemical Society Table 1. Optimization of the Asymmetric α-Amino Radical Additiona

successful reaction; N,N-dimethyl aniline produces only a trace of the conjugate addition product (entry 15), consistent with our design strategy. Second, we observed the formation of 52% yield of 3b after 18 h even in the absence of Lewis acid (entry 16). Thus, the rate acceleration afforded by the Lewis acid catalyst must be large enough to overcome a significant racemic background addition in the absence of Lewis acid catalyst. Table 2 summarizes the effects of structurally varied αsilylamines under the optimized conditions for enantioselective Table 2. Reactions of Structurally Varied α-Silylamines with Michael Acceptor 2ba




[Ru] mol %


yield (%)b

ee (%)c

1d,e 2d 3d 4d 5d 6 7 8 9 10 11 12 13 14 15f 16e 17 18

2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2b 2b 2b 2b

none tBuPybox (4a) BnPybox (4b) iBuPybox (4c) sBuPybox (4d) sBuPybox (4d) sBuPybox (4d) sBuPybox (4d) sBuPybox (4d) sBuPybox (4d) sBuPybox (4d) sBuPybox (4d) sBuPybox (4d) iBuPybox (4c) iBuPybox (4c) none iBuPybox (4c) iBuPybox (4c)

2% 2% 2% 2% 2% 2% 5% 15% 2% 2% 2% 2% 2% 2% 2% 2% 0% 2%

none none none none none none none none KCl Bu4N+Cl− Bu4N+PF6− Bu4N+ClO4− Bu4N+Cl− Bu4N+Cl− Bu4N+Cl− Bu4N+Cl− Bu4N+Cl− none

28 18 75 15 70 94 93 97 74 91 52 40 80 83

Enantioselective conjugate additions of α-amino radicals via cooperative photoredox and Lewis acid catalysis.

We report the highly enantioselective addition of photogenerated α-amino radicals to Michael acceptors. This method features a dual-catalyst protocol ...
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